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C Cordon-Cardo

Publications and source records attributed to C Cordon-Cardo.

At least 181 records · Page 10Linked to original sources
PubMed1993

[DNA analysis in stomach cancer--correlation of aneuploidy with tumor site].

The DNA status and the proliferative activity was determined in 37 gastric carcinomas applying computerized image analysis. Aneuploidy was found in 51.4% (n = 19) of the tumors. Comparing diploid and aneuploid lesions the latter ones had statistically significant increased DNA amount, DNA index and proliferative rate (7.4 pg, 1.03 and 16.4% versus 12.8 pg, 1.78 and 30.7%; p < 0.05). Aneuploidy occurred more frequently in tumors at proximal sites (p < 0.05), but was not associated with histological type, differentiation and tumor stage. The prognostic impact of DNA aneuploidy remains controversial, since tumor aggressiveness per se is not directly related to aneuploidy.

Adult↗
PubMed1992

Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer.

BACKGROUND: It has been reported that 50%-70% of patients with bladder cancer experience recurrence after initial successful treatment and about 10%-20% of these patients die of the disease. Despite precise pathologic staging and grading, we are unable to predict clinical outcome in all patients. The retinoblastoma-susceptibility (RB) gene, a prototype of tumor suppressor genes, has recently been associated with development and/or progression of bladder cancer, as well as sarcoma and small-cell lung cancer. In transitional cell carcinomas of the bladder, we have observed altered expression of the Rb gene product--a nuclear phosphoprotein thought to function as a cell cycle regulator. PURPOSE: The aim of this study was to investigate the hypothesis that altered patterns of Rb expression correlate with prognosis in bladder cancer. METHODS: Expression of the RB gene was evaluated in specimens from 48 primary bladder tumors obtained by cystectomy or transurethral resection. Rb protein expression was correlated with disease outcome in these patients. Rb expression was examined by immunohistochemistry, using the mouse monoclonal antibody Rb-PMG3-245 on frozen tissue sections. Computerized image analysis was used to quantify the level of Rb protein in individual tumor cells. RESULTS: The overall 5-year disease-free survival was 66%, with a median follow-up of 42 months. Normal levels of Rb protein expression were found in 34 patients (Rb-positive group). A spectrum of altered patterns of expression from undetectable levels to heterogeneous expression, however, was observed in 14 patients (altered Rb group). Of the 38 patients with muscle-invasive tumors, 13 were categorized as having altered expression of Rb protein. Only one of 10 patients with superficial carcinomas had altered expression of Rb protein. The 5-year survival was significantly decreased in patients with altered Rb protein compared with the survival in patients with positive Rb expression (P less than .001). CONCLUSIONS: The results suggest that tumors exhibiting decreased expression of the RB gene-coded product (Rb protein) had a more aggressive biological behavior than those that expressed the Rb protein in the majority of their tumor cells. IMPLICATIONS: This study demonstrates that altered patterns of Rb protein expression may be an important prognostic variable in patients presenting with invasive bladder cancer.

Adult↗
PubMed1992

Expression of disialogangliosides GD2 and GD3 on human soft tissue sarcomas.

METHODS: Fifty-six freshly frozen human sarcomas were studied for expression of disialogangliosides by avidin-biotin immunohistochemical staining with purified monoclonal antibodies (MoAb) 3F8 (antidisialoganglioside GD2) and R24 (antidisialoganglioside GD3). RESULTS: Ninety-three percent of the tumors tested by the immunohistochemical staining expressed GD2 and 88% expressed GD3. The intensity of expression varied among sarcomas of different histologic types. Liposarcoma, fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, and spindle cell sarcoma reacted strongly with 3F8 and R24. Embryonal rhabdomyosarcoma and synovial sarcoma demonstrated substantially weaker staining by either MoAb. Weakly reactive or nonreactive tumors were, in general, high-grade or metastatic sarcomas. Ganglioside extraction and thin-layer chromatography/immunothin-layer chromatography of two liposarcomas confirmed the identities of these gangliosides. CONCLUSIONS: GD2 and GD3 may indicate sites for MoAb-targeted imaging and therapy for sarcomas. The association of a diminished stainability by 3F8 and R24 with aggressive sarcomas may indicate prognostic significance.

Gangliosides↗
PubMed1992

Blood group antigens in normal and neoplastic urothelium.

The ABO and Lewis blood group antigens are cell surface carbohydrate determinants formed by the sequential addition of saccharides to precursor backbone structures of membrane lipids and proteins. Suppression of normally active glycosyltransferases results in the absence of antigens that are normally expressed. ABH antigen deletion in malignant and premalignant urothelium has been extensively evaluated; it appears to correlate with significantly higher rates of tumor recurrence and disease progression. However, we have recently shown that the ABH blood group system is differentially expressed in the normal urothelium of secretors in contrast to nonsecretor individuals. The normal urothelium of nonsecretors does not express A, B or H determinants; therefore, deletion of ABH antigens can only be ascertained in secretor individuals. Although nonsecretors only comprise 22-24% of the population, this observation mandates a reevaluation of earlier studies. Deletion of A, B or H antigens is noted in carcinoma in situ (CIS), and in invasive and metastatic transitional cell carcinoma (TCC) of secretor individuals. Increased synthesis or activation of normally quiescent glycosyltransferases in bladder tumors can result in the expression of aberrant tumor-associated blood group antigens. Immunohistochemical analysis has demonstrated that Lewis X (Le(x)) is not detected in normal adult urothelium except for occasional umbrella cells. However, papillomas, CIS and TCC expressed Le(x) in 84% of cases, regardless of grade, stage, blood type or secretor status of the individual. The presence of Le(x)-positive cells in bladder lavage specimens enhanced the detection of urothelial tumor cells, correctly identifying bladder tumors in 253/293 (86%) cases compared to a 63% sensitivity for cytology alone.(ABSTRACT TRUNCATED AT 250 WORDS)

ABO Blood-Group System↗
PubMed1992

P-glycoprotein expression in brain tumors.

Overexpression of P-glycoprotein (P-gp) in cancer cells can result in resistance to several chemotherapy agents (multidrug resistance) including doxorubicin and vincristine. The drugs to which resistance develops also penetrate the blood brain barrier poorly. P-gp expression in brain capillary endothelial cells suggests that P-gp may restrict drug entry into brain tumors and thus be another mechanism of drug resistance. To seek evidence for either of these roles in the drug resistance of brain tumors, we examined the location of expression of P-gp in 49 brain tumors, using an anti-P-gp mouse monoclonal antibody and immunohistochemistry. P-gp expression was observed in tumor cells of two glioblastomas and a meningeal sarcoma but not in low-grade primary or metastatic tumors. In low-grade primary tumors, P-gp was present in all vascular endothelial cells. In the vascular endothelial cells of anaplastic primary brain tumors and brain metastases, P-gp expression was heterogeneous or absent. These findings are consistent with a role for P-gp in the resistance of some brain tumors to chemotherapy agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Expression of Her2/neu oncogene product p185 in correlation to clinicopathological and prognostic factors of gastric carcinoma.

The expression of the Her2/neu gene product p185 was retrospectively analyzed in 58 patients with gastric carcinoma. The results were correlated to various clinicopathological and prognostic factors. Positive membrane staining for p185 could be detected in 38% of the patients (22/58). Membrane staining was significantly greater in well and moderately differentiated tumors of the intestinal type when compared with poorly differentiated lesions and carcinomas of the diffuse type (P less than 0.01). Positive membrane staining did not correlate with site and tumor stage, but T1 lesions had less membrane staining than more advanced primary tumors. Overall survival showed no difference between p185-positive and negative cases. Multivariate analysis defined a subgroup of curatively resected patients with stage III and IV disease that had a statistically significant poorer survival when p185 was overexpressed (P = 0.005). Overexpression of the Her2/neu product p185 appears to be associated with intestinal-type gastric carcinoma and may help in identifying a subset of patients at increased risk for shorter survival.

Adenocarcinoma↗
PubMed1992

Treatment with high dose mouse monoclonal (anti-GD3) antibody R24 in patients with metastatic melanoma.

R24 is a mouse IgG3 monoclonal antibody that reacts with the ganglioside GD3 expressed by melanoma cells and other cells of neuroectodermal origin (e.g. adrenal medulla). Antitumour activity of R24 was demonstrated in initial phase I and pilot trials, but treatment was limited by urticaria at cumulative doses of 400 mg/m2. A trial exploring intensification of the dose of R24 was conducted in eight patients. Planned doses of R24 antibody were 800 and 1200 mg/m2 over 6-8 days by continuous i.v. infusion. All patients received concomitant therapy with hydroxyzine hydrochloride and cimetidine to minimize urticaria. One patient developed anaphylaxis, after which no further therapy was given. All patients developed peripheral blood lymphopenia and marked decreases in serum complement values during treatment, suggesting depletion of two possible effector mechanisms of the antitumour effects of R24. A vascular leak syndrome, manifested by weight gain, oedema and hypotension, was evident in seven patients during the initial 24-36 h of treatment. Serum sickness syndrome was observed in six of seven evaluable patients between days 5 and 8, coincident with the onset of the human anti-globulin response to R24. One patient given 1200 mg/m2 had a minor response (38% reduction in pelvic nodes) lasting 12 months. There was no detectable increase (by immunohistochemical staining) in deposition of R24 within tumour sites at doses used in this trial compared to that observed at doses of 240 and 400 mg/m2. The maximum tolerated dose was 800 mg/m2. Dose-limiting toxicity was manifest as reversible hypertension with end-organ symptoms (chest pain or visual field defects) in patients treated with a dose of 1200 mg/m2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Expression of P-glycoprotein in normal muscle cells and myogenic tumors.

We have analyzed the expression of the multidrug resistance (mdr-1) gene product, P-glycoprotein, by immunohistochemical staining of frozen tissue sections of human normal muscle fibers and 31 tissue specimens of cases of myogenic sarcomas. The objective of this study was to further characterize what appears to be a variety of responses to therapy in like-appearing but distinct tumors. We have used two mouse monoclonal antibodies that recognize two different epitopes of P-glycoprotein. Mouse monoclonal antibody HYB-241 detects an extracellular epitope of P-glycoprotein, whereas C219 detects a carboxy-terminal intracellular epitope and has recently been reported to cross-react with the mdr-3 gene product. Differential epitope expression was observed among normal muscle fibers with the two antibodies used. Smooth-muscle cells were unreactive for the two antibodies, whereas cardiac and a subgroup of skeletal muscle fibers were intensely stained by C219, but not by HYB-241. P-glycoprotein expression was observed in 23% of the 31 myogenic sarcomas analyzed. Our study was conducted mainly using adult myogenic sarcomas (28 out of 31 cases), with a few cases (three out of 31 cases) of childhood sarcomas. Nineteen tumors were leiomyosarcomas, seven cases were embryonal rhabdomyosarcomas, and five cases were rhabdomyosarcomas. We have considered expression of the mdr-1-coded P-glycoprotein when we observed either HYB-241 and C219 staining, or just HYB-241 immunoreactivities. Although P-glycoprotein expression can now be detected in human sarcomas, further studies are needed, mainly comparing tumor samples before, during, and after therapy, to establish the possible significance of the P-glycoprotein expression in clinical drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

The expression of the Hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues.

Using immunohistochemistry or Western blot analysis, the authors have studied the expression of the Hu antigen (a neuronal protein identified by the serum of patients with small cell lung cancer and paraneoplastic encephalomyelitis/sensory neuronopathy) in normal human tissues and 115 tumors of different histologic types. In normal tissue, the Hu antigen is highly restricted to the nervous system. In lung tumors, the Hu antigen is restricted in its expression to all small cell carcinomas. A few other neuroendocrine-related tumors, especially neuroblastomas (50%), also express the antigen.

Carcinoma, Small Cell↗
PubMed1992

Immunopathologic analysis of human urinary bladder cancer. Characterization of two new antigens associated with low-grade superficial bladder tumors.

The authors have further characterized the normal human tissue distribution and tumor expression of two highly restricted tumor-associated antigens, detected by mouse monoclonal antibodies M344 and 19A211, which are primarily expressed on low-grade superficial urinary bladder tumors. This study was conducted using immunohistochemical staining of frozen and deparaffinized sections of human normal and tumor tissues. The antigens are stable and well preserved on deparaffinized tissue sections. M344 antibody identifies a high-molecular-weight determinant on a cytosolic protein component of over 300,000 Mr. This antigen was not detected on any normal tissue analyzed, including 14 specimens of normal urothelium and 22 cases of cystitis; however, M344 was positive in 74.5% of Ta-T1 tumors and 11% of T3-T4 tumors. 19A211 antibody identifies a sialylated epitope on a cytoplasmic protein complex of 100,000 to 200,000 Mr. This antigen also was expressed preferentially on low-grade superficial bladder tumors (77% Ta-T1) and less frequently on deeply infiltrating tumors (10% T3-4). 19A211 was negative on all normal cells tested, with the exception of umbrella cells, in approximately 25% of the normal urothelium and cystitis specimens studied. Either one or both of these tumor-associated antigens are detected in approximately 80% of low-grade papillary superficial tumors and carcinoma in situ of the urinary bladder. The expression of these antigens on a subset of low-grade bladder tumors, known to progress in only about 10% of cases, suggests that phenotypic differences may reflect biologic potential. Beyond their possible biologic significance, antibodies M344 and 19A211 may provide clinically useful probes for early detection and stratification of urinary bladder tumors.

Antibodies, Monoclonal↗
PubMed1991

Expression of HLA-A,B,C antigens on primary and metastatic tumor cell populations of human carcinomas.

The expression of monomorphic determinants of the histocompatibility leukocyte antigens (HLA) class I antigens by human malignant tumor cells was studied in tissue specimens of 70 primary tumor lesions obtained from patients with carcinoma of the breast (41 patients), colon (8 patients), urinary bladder (8 patients), and kidney (13 patients), and in samples of either synchronous or metachronous lymph node, lung, or liver metastases available in 44 of the patients. The frequencies of HLA class I expressor and nonexpressor tumor cells were determined by immunohistochemical staining of histological sections of fresh frozen tissue samples with the W6/32 monoclonal antibody. The tumor cell populations in the majority of the primary lesions consisted predominantly of HLA-immunoreactive cells (observed in 38 of 70 patients; 54%), especially in those patients who did not have clinical evidence of metastatic disease (8 of 11 patients; 73%). Various degrees of loss of reactivity were observed in other primary lesions, although in only 8 (12%) tumors (7 of which were obtained from patients with metastatic disease), the neoplastic cells were nearly exclusively HLA-nonreactive. In contrast, the majority of metastatic lesions consisted of either predominantly HLA-negative cells (33 of 44 specimens; 75%) or mixed populations (10 of 44 specimens; 23%), whereas only one metastatic lesion manifested HLA class I antigen staining in more than 70% of its tumor cells (P = 0.0005). Intravascular clusters of tumor cells consisted predominantly of HLA class I nonexpressors. The observed patterns of distribution of HLA expressors and nonexpressor tumor cells are compatible with the notion that HLA-negative cells in human carcinomas manifest a selective advantage with regard to metastatic progression and growth. The suppressed expression of major histocompatibility complex class I antigens on metastatic cells may lead to failure of presentation of cell surface tumor specific epitopes to host cytotoxic T-lymphocytes. Such a process would enable tumor cells to evade host immune responses and would promote and enhance cell dissemination and metastatic growth.

Antibodies, Monoclonal↗
PubMed1991

Molecular genetic alterations in superficial and locally advanced human bladder cancer.

We attempted to define the role of tumor suppressor genes in the pathogenesis of human bladder cancer through a combined molecular genetic and immunohistochemical approach. Thirty-four bladder tumors (1 Pis, 6 Pa, 5 P1, 3 P3a, 18 P3b, 1 P4; 8 low grade and 26 high grade tumors) have been analyzed. Restriction fragment length polymorphism analysis directed at 5 suspected or established tumor suppressor gene regions (3p21-25, 11p15, 13q14, 17p11-13, and 18q21) was combined with immunohistochemical using Rb-PMG3-245 monoclonal antibody directed at the retinoblastoma (Rb) gene product. Tumor grade correlated with deletions of 3p (P = 0.004) and 17p (P = 0.063). Tumor stage correlated with deletions of 3p (P = 0.010), 17p (P = 0.015) and altered Rb expression (P = 0.054). Vascular invasion correlated only with deletions of 17p (P = 0.038). No marker correlated with positive lymph nodes. Our results suggest that altered Rb expression occurs in all grades and stages of bladder cancer but is more commonly associated with invasive tumors. Genetic alterations of 3p, 11p, 17p, and 18q are rare events in low grade, superficial tumors, whereas they are more common in high grade and invasive bladder cancer. The role of these genetic alterations in the prognosis of bladder cancer will require additional follow-up and further studies.

Blotting, Southern↗
PubMed1991

Correlation between retinoblastoma gene expression and differentiation in human testicular tumors.

Inactivation of the retinoblastoma gene (RB gene) is associated with the development of several human malignancies including retinoblastomas, some osteo- and soft tissue sarcomas, small cell lung cancer, and possibly breast and bladder cancers. To our knowledge, this gene has not been evaluated in human germ-cell malignancies. In this study 67 primary testicular germ-cell tumors and 4 testicular non-germ-cell malignancies were examined to determine the prevalence and nature of RB gene alterations. Decreased expression of RB gene mRNA was found in all testicular germ-cell tumors (both seminomas and nonseminomas) examined. The RB protein could not be detected by immunohistochemical analysis in the undifferentiated cells of any germ-cell tumors whereas the differentiated malignant cells present in 14/15 teratocarcinomas expressed the protein. No gross alterations of the RB gene were found at DNA level in any of the examined specimens. This and the presence of the RB protein in the more differentiated tumor cells of teratocarcinomas suggest that changes in transcript levels rather than mutation(s) of the gene may be responsible for the absent or decreased RB expression in human germ-cell tumors. To date studies on the mechanism of RB regulation have demonstrated that it occurs at the protein level by phosphorylation of the p105 gene product. The findings presented here indicate that additional regulation might occur at the transcript level.

Blotting, Southern↗
PubMed1991

The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3.

trkB is a tyrosine protein kinase gene highly related to trk, a proto-oncogene that encodes a receptor for nerve growth factor (NGF) and neurotrophin-3 (NT-3). trkB expression is confined to structures of the central and peripheral nervous systems, suggesting it also encodes a receptor for neurotrophic factors. Here we show that brain-derived neurotrophic factor (BDNF) and NT-3, but not NGF, can induce rapid phosphorylation on tyrosine of gp145trkB, one of the receptors encoded by trkB. BDNF and NT-3 can induce DNA synthesis in quiescent NIH 3T3 cells that express gp145trkB. Cotransfection of plasmids encoding gp145trkB and BDNF or NT-3 leads to transformation of recipient NIH 3T3 cells. In these assays, BDNF elicits a response at least two orders of magnitude higher than NT-3. Finally, 125I-NT-3 binds to NIH 3T3 cells expressing gp145trkB; binding can be competed by NT-3 and BDNF but not by NGF. These findings indicate that gp145trkB may function as a neurotrophic receptor for BDNF and NT-3.

Animals↗
PubMed1991

The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3.

The product of the trk proto-oncogene encodes a receptor for nerve growth factor (NGF). Here we show that NGF is a powerful mitogen that can induce resting NIH 3T3 cells to enter S phase, grow in semisolid medium, and become morphologically transformed. These mitogenic effects are absolutely dependent on expression of gp140trk receptors, but do not require the presence of the previously described low affinity NGF receptor. gp140trk also serves as a receptor for the related factor neurotrophin-3 (NT-3), but not for brain-derived neurotrophic factor. Both NGF and NT-3 induce the rapid phosphorylation of gp140trk receptors and the transient expression of c-Fos proteins. However, NT-3 appears to elicit more limited mitogenic responses than NGF. These results indicate that the product of the trk proto-oncogene is sufficient to mediate signal transduction processes induced by NGF and NT-3, at least in proliferating cells.

Animals↗
PubMed1991

DNA, RNA and immunohistochemical characterization of the HER-2/neu oncogene in transitional cell carcinoma of the bladder.

HER-2/neu overexpression appears to play a role in determining the malignant potential of some human cancers. To date, no urothelial malignancies appear to have been evaluated for HER-2/neu DNA amplification, mRNA expression and protein overproduction. By Southern hybridization we detected DNA amplification and a possible structural rearrangement of the HER-2/neu oncogene in one of 12 bladder tumors. A 14 kb DNA fragment in addition to the expected 12.5 Kb fragment was found. Additionally, the HER-2/neu oncogene was amplified sixfold in the tumor compared to placental DNA. Five of 14 (36%) bladder tumors overexpressed HER-2/neu mRNA three to 38-fold compared to normal urothelium. HER-2/neu overexpression occurred in superficial and invasive tumors. Immunohistochemical analysis was performed on the one tumor with DNA amplification and the 14 tumors evaluated for mRNA expression. The tumor with DNA amplification and three of the five tumors with HER-2/neu mRNA overexpression stained positively for the p185HER-2/neu protein. These findings suggest that DNA amplification occurs infrequently in bladder cancer. Thirty-six percent of bladder cancers overexpress HER-2/neu mRNA. Immunohistochemical analysis with a p185HER-2/neu polyclonal antibody, on formalin fixed, paraffin embedded tissue, was specific for HER-2/neu overexpression but not as sensitive as Northern analysis.

Blotting, Northern↗
PubMed1991

On the origins of clinical drug resistance.

Recent progress in understanding the clinical importance of certain laboratory models of drug resistance is cause for clinical oncologists to rethink some of the current concepts used in developing chemotherapy programs. The following discussion will reexamine a popular model of resistance development and highlight certain insights gained from clinical and laboratory studies of multidrug resistance. Such insights both challenge traditional concepts of cancer treatment and suggest new therapeutic approaches that would otherwise not have been apparent.

ATP Binding Cassette Transporter, Subfamily B, Mem↗